In collaboration with several Principal Investigators at the CCR/NCI, in silico screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the CADD Group's resources, including our screening databases to generate lists of compounds to be purchased from commercial suppliers, with the goal of obtaining novel lead compounds in in vitro and/or cell-based assays. Currently, we are predominantly working on the targets Akt (PH domain), in collaboration with Phillip Dennis, Cancer Therapeutics Branch, CCR, NCI;c-Met, in collaboration with Donald Bottaro, Urologic Oncology Branch, CCR, NCI, and Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI;polo-Box domain of polo-like kinase 1, in collaboration with Kyung S. Lee, Laboratory of Metabolism, CCR, NCI;Grb2 SH2 domain, in collaboration with Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI;PKC, in collaboration with Peter Blumberg, Laboratory of Cancer Biology and Genetics, CCR, NCI, and Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI;herpes thymidine kinase, in collaboration with Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI;bis-imidazoacridone DNA intercalators, in collaboration with Sergey Tarasov, Structural Biophysics Laboratory, CCR, NCI;small-molecule mimetics of a surface patch of thrombospondin-1 (TSP1) interacting with CD47, in collaboration with David D. Roberts, Laboratory of Pathology, CCR, NCI;the interaction of the transcription factor HIF-1 alpha with cofactor p300, in collaboration with William Douglas Figg Sr., Medical Oncology Branch, CCR, NCI;the aberrant chimeric transcription factor ASPL-TFE3, in collaboration with Robert H. Shoemaker, Screening Technologies Branch, DTP, DCTD, NCI;the development of targeted therapy for CBF leukemias by targeting the CBF-beta and Runx1 interaction, in collaboration with Paul Liu, NHGRI, NIH;the modeling of the interactions of tocopherols and retinol with the active site of CYP2C9, in collaboration with Demetrius Albanes, M.D., Nutritional Epidemiology Branch, NCI;CADD work for the development of HIV-1 Rev inhibitors, in collaboration with Christoph Rader, Antibody Technology Section, ETIB, CCR, NCI;and in silico screening and modeling support for screening for SUMOylation inhibitors, in collaboration with John S. Schneekloth, Jr., CBL, CCR, NCI. For Akt, c-Met, the polo-Box domain of plk1, Tdp1, and TSP1/CD47, initial hit sets have been generated, screening samples purchased, and these samples assayed by our collaborators. Inhibitory activity was found for a number of samples in each one of these assay. Sample sets have been proposed for purchase for the HSP90 project. These efforts have resulted in several patent applications and/or patents granted with CADD Group members a co-inventors.